Hash-based efficient comparison of sequencing results

ABSTRACT

First and second sequenced outputs are accessed. The sequenced outputs contain variants occurring at different carriers and at different carrier positions. Hashes are generated over a selected pattern length of positions for those carrier positions that are shared between the sequenced outputs to produce window hashes for base patterns in first and second sequences. Each sequence is based on the shared carrier positions and the respective sequenced output. The window hashes are non-unique. Window hashes that occur less than a ceiling number times are selected. The selected window hashes are compared between the sequences on a starting position basis such that selected window hashes for base patterns having same start positions in the sequenced outputs are compared. Common window hashes are identified between the sequences based on the comparing. A similarity measure is determined between the sequences based on the common window hashes.

PRIORITY APPLICATIONS

This application is a continuation of U.S. Pat. Application No.16/575,278, titled “ORDINAL POSITION-SPECIFIC AND HASH-BASED EFFICIENTCOMPARISON OF SEQUENCING RESULTS”, filed Sep. 18, 2019 (Attorney DocketNo. DCAI 1001-6), which claims priority to or the benefit of U.S.Provisional Pat. Application No. 62/734,840, titled, “HASH-BASEDEFFICIENT COMPARISON OF SEQUENCING RESULTS,” filed Sep. 21, 2018(Attorney Docket No. DCAI 1001-1); U.S. Provisional Pat. Application No.62/734,872, titled, “BIN-SPECIFIC AND HASH-BASED EFFICIENT COMPARISON OFSEQUENCING RESULTS,” filed Sep. 21, 2018 (Attorney Docket No. DCAI1001-2); and U.S. Provisional Pat. Application No. 62/734,895, titled,“ORDINAL POSITION-SPECIFIC AND HASH-BASED EFFICIENT COMPARISON OFSEQUENCING RESULTS,” filed Sep. 21, 2018 (Attorney Docket No. DCAI1001-3). The foregoing applications are hereby incorporated by referencein their entirety for all purposes.

CROSS-REFERENCE TO OTHER APPLICATIONS

The following materials are incorporated by reference as if fully setforth herein:

U.S. Pat. Application No. 16/575,276, titled “HASH-BASED EFFICIENTCOMPARISON OF SEQUENCING RESULTS,” filed Sep. 18, 2019, (Atty. DocketNo. DCAI 1001-4); and

U.S. Pat. Application No. 16/575,277, titled “BIN-SPECIFIC ANDHASH-BASED EFFICIENT COMPARISON OF SEQUENCING RESULTS,” filed Sep. 18,2019, (Atty. Docket No. DCAI 1001-5).

FIELD OF THE TECHNOLOGY DISCLOSED

The technology disclosed relates to artificial intelligence typecomputers and digital data processing systems and corresponding dataprocessing methods and products for emulation of intelligence (i.e.,knowledge based systems, reasoning systems, and knowledge acquisitionsystems); and including systems for reasoning with uncertainty (e.g.,fuzzy logic systems), adaptive systems, machine learning systems, andartificial neural networks. In particular, the technology disclosedrelates to using hashing to compare sequences.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

The color drawings also may be available in PAIR via the SupplementalContent tab. In the drawings, like reference characters generally referto like parts throughout the different views. Also, the drawings are notnecessarily to scale, with an emphasis instead generally being placedupon illustrating the principles of the technology disclosed. In thefollowing description, various implementations of the technologydisclosed are described with reference to the following drawings, inwhich:

FIG. 1 is a block diagram that shows various aspects of the technologydisclosed.

FIG. 2 illustrates a phased encoding scheme with sixteen phased pairingsthat are used to encode the variant data.

FIG. 3 shows an unphased encoding scheme with ten unphased pairings thatcan also be used to encode the variant data.

FIG. 4 depicts first and second sequenced files that contain variantsoccurring at different carriers and at different carrier positions.

FIG. 5 illustrates a reference array for those carrier positions thatare shared between the first and second sequenced files. FIG. 5 alsoillustrates first and second sequences respectively generated from thefirst and second sequenced files based on the reference array.

FIG. 6 shows how hashes are generated over a selected pattern length ofpositions in the reference array to independently produce non-uniquewindow hashes for base patterns in the first and second sequences.

FIG. 7 depicts various hashing implementations of the technologydisclosed, including global genome hashing, location sensitive hashing,and location tagged hashing.

FIG. 8 is one implementation of a distance tree visualization.

FIG. 9 shows an example bin-wise comparison between genomes of twoindividuals as implemented by the location sensitive hashing.

FIG. 10 illustrates one implementation of determining ethnic ancestry orethnic origins of an individual using the location sensitive hashingand/or the location tagged hashing.

FIGS. 11A, 11B, and 11C show one implementation of a genomic browserthat presents comparative visualizations of genomic content of twoindividuals.

FIG. 12 is a simplified block diagram of a computer system that can beused to implement the technology disclosed.

DETAILED DESCRIPTION

The following discussion is presented to enable any person skilled inthe art to make and use the technology disclosed, and is provided in thecontext of a particular application and its requirements. Variousmodifications to the disclosed implementations will be readily apparentto those skilled in the art, and the general principles defined hereinmay be applied to other implementations and applications withoutdeparting from the spirit and scope of the technology disclosed. Thus,the technology disclosed is not intended to be limited to theimplementations shown, but is to be accorded the widest scope consistentwith the principles and features disclosed herein.

Terminology

A base refers to a nucleotide base or nucleotide, A (adenine), C(cytosine), T (thymine), or G (guanine).

The term “chromosome” refers to the heredity-bearing gene carrier of aliving cell, which is derived from chromatin strands comprising DNA andprotein components (especially histones). The conventionalinternationally recognized individual human genome chromosome numberingsystem is employed herein. This application uses the terms “chromosome”and “carrier” interchangeably.

The term “site” refers to a unique position (e.g., chromosome ID,chromosome position and orientation) on a reference genome. In someimplementations, a site may be a residue, a sequence tag, or a segment’sposition on a sequence. The term “locus” may be used to refer to thespecific location of a nucleic acid sequence or polymorphism on areference chromosome. This application uses the terms “site” and“position” interchangeably.

The term “sample” herein refers to a sample, typically derived from abiological fluid, cell, tissue, organ, or organism containing a nucleicacid or a mixture of nucleic acids containing at least one nucleic acidsequence that is to be sequenced and/or phased. Such samples include,but are not limited to sputum/oral fluid, amniotic fluid, blood, a bloodfraction, fine needle biopsy samples (e.g., surgical biopsy, fine needlebiopsy, etc.), urine, peritoneal fluid, pleural fluid, tissue explant,organ culture and any other tissue or cell preparation, or fraction orderivative thereof or isolated therefrom. Although the sample is oftentaken from a human subject (e.g., patient), samples can be taken fromany organism having chromosomes, including, but not limited to dogs,cats, horses, goats, sheep, cattle, pigs, etc. The sample may be useddirectly as obtained from the biological source or following apretreatment to modify the character of the sample. For example, suchpretreatment may include preparing plasma from blood, diluting viscousfluids and so forth. Methods of pretreatment may also involve, but arenot limited to, filtration, precipitation, dilution, distillation,mixing, centrifugation, freezing, lyophilization, concentration,amplification, nucleic acid fragmentation, inactivation of interferingcomponents, the addition of reagents, lysing, etc.

The term “sequence” includes or represents a strand of nucleotidescoupled to each other. The nucleotides may be based on DNA or RNA. Itshould be understood that one sequence may include multiplesub-sequences. For example, a single sequence (e.g., of a PCR amplicon)may have 350 nucleotides. The sample read may include multiplesub-sequences within these 350 nucleotides. For instance, the sampleread may include first and second flanking subsequences having, forexample, 20-50 nucleotides. The first and second flanking sub-sequencesmay be located on either side of a repetitive segment having acorresponding sub-sequence (e.g., 40-100 nucleotides). Each of theflanking sub-sequences may include (or include portions of) a primersub-sequence (e.g., 10-30 nucleotides). For ease of reading, the term“sub-sequence” will be referred to as “sequence,” but it is understoodthat two sequences are not necessarily separate from each other on acommon strand. To differentiate the various sequences described herein,the sequences may be given different labels (e.g., target sequence,primer sequence, flanking sequence, reference sequence, and the like).Other terms, such as “allele,” may be given different labels todifferentiate between like objects.

The term “reference genome” or “reference sequence” refers to anyparticular known genome sequence, whether partial or complete, of anyorganism which may be used to reference identified sequences from asubject. For example, a reference genome used for human subjects as wellas many other organisms is found at the National Center forBiotechnology Information at ncbi.nlm.nih.gov. A “genome” refers to thecomplete genetic information of an organism or virus, expressed innucleic acid sequences. A genome includes both the genes and thenoncoding sequences of the DNA. The reference sequence may be largerthan the reads that are aligned to it. For example, it may be at leastabout 100 times larger, or at least about 1000 times larger, or at leastabout 10,000 times larger, or at least about 105 times larger, or atleast about 106 times larger, or at least about 107 times larger. In oneexample, the reference genome sequence is that of a full length humangenome. In another example, the reference genome sequence is limited toa specific human chromosome such as chromosome 13. In someimplementations, a reference chromosome is a chromosome sequence fromhuman genome version hg19. Such sequences may be referred to aschromosome reference sequences, although the term reference genome isintended to cover such sequences. Other examples of reference sequencesinclude genomes of other species, as well as chromosomes,sub-chromosomal regions (such as strands), etc., of any species. Invarious implementations, the reference genome is a consensus sequence orother combination derived from multiple individuals. However, in certainapplications, the reference sequence may be taken from a particularindividual.

The term “read” refer to a collection of sequence data that describes afragment of a nucleotide sample or reference. The term “read” may referto a sample read and/or a reference read. Typically, though notnecessarily, a read represents a short sequence of contiguous base pairsin the sample or reference. The read may be represented symbolically bythe base pair sequence (in ATCG) of the sample or reference fragment. Itmay be stored in a memory device and processed as appropriate todetermine whether the read matches a reference sequence or meets othercriteria. A read may be obtained directly from a sequencing apparatus orindirectly from stored sequence information concerning the sample. Insome cases, a read is a DNA sequence of sufficient length (e.g., atleast about 25 bp) that can be used to identify a larger sequence orregion, e.g., that can be aligned and specifically assigned to achromosome or genomic region or gene.

Next-generation sequencing methods include, for example, sequencing bysynthesis technology (Illumina), pyrosequencing (454), ion semiconductortechnology (Ion Torrent sequencing), single-molecule real-timesequencing (Pacific Biosciences) and sequencing by ligation (SOLiDsequencing). Depending on the sequencing methods, the length of eachread may vary from about 30 bp to more than 10,000 bp. For example,Illumina sequencing method using SOLiD sequencer generates nucleic acidreads of about 50 bp. For another example, Ion Torrent Sequencinggenerates nucleic acid reads of up to 400 bp and 454 pyrosequencinggenerates nucleic acid reads of about 700 bp. For yet another example,single-molecule real-time sequencing methods may generate reads of10,000 bp to 15,000 bp. Therefore, in certain implementations, thenucleic acid sequence reads have a length of 30-100 bp, 50-200 bp, or50-400 bp.

The terms “sample read”, “sample sequence” or “sample fragment” refer tosequence data for a genomic sequence of interest from a sample. Forexample, the sample read comprises sequence data from a PCR ampliconhaving a forward and reverse primer sequence. The sequence data can beobtained from any select sequence methodology. The sample read can be,for example, from a sequencing-by-synthesis (SBS) reaction, asequencing-by-ligation reaction, or any other suitable sequencingmethodology for which it is desired to determine the length and/oridentity of a repetitive element. The sample read can be a consensus(e.g., averaged or weighted) sequence derived from multiple samplereads. In certain implementations, providing a reference sequencecomprises identifying a locus-of-interest based upon the primer sequenceof the PCR amplicon.

The term “raw fragment” refers to sequence data for a portion of agenomic sequence of interest that at least partially overlaps adesignated position or secondary position of interest within a sampleread or sample fragment. Non-limiting examples of raw fragments includea duplex stitched fragment, a simplex stitched fragment, a duplexun-stitched fragment and a simplex un-stitched fragment. The term “raw”is used to indicate that the raw fragment includes sequence data havingsome relation to the sequence data in a sample read, regardless ofwhether the raw fragment exhibits a supporting variant that correspondsto and authenticates or confirms a potential variant in a sample read.The term “raw fragment” does not indicate that the fragment necessarilyincludes a supporting variant that validates a variant call in a sampleread. For example, when a sample read is determined by a variant callapplication to exhibit a first variant, the variant call application maydetermine that one or more raw fragments lack a corresponding type of“supporting” variant that may otherwise be expected to occur given thevariant in the sample read.

The terms “mapping”, “aligned,” “alignment,” or “aligning” refer to theprocess of comparing a read or tag to a reference sequence and therebydetermining whether the reference sequence contains the read sequence.If the reference sequence contains the read, the read may be mapped tothe reference sequence or, in certain implementations, to a particularlocation in the reference sequence. In some cases, alignment simplytells whether or not a read is a member of a particular referencesequence (i.e., whether the read is present or absent in the referencesequence). For example, the alignment of a read to the referencesequence for human chromosome 13 will tell whether the read is presentin the reference sequence for chromosome 13. A tool that provides thisinformation may be called a set membership tester. In some cases, analignment additionally indicates a location in the reference sequencewhere the read or tag maps to. For example, if the reference sequence isthe whole human genome sequence, an alignment may indicate that a readis present on chromosome 13, and may further indicate that the read ison a particular strand and/or site of chromosome 13.

The term “variant” refers to a nucleic acid sequence that is differentfrom a nucleic acid reference. Typical nucleic acid sequence variantincludes without limitation single nucleotide polymorphism (SNP), shortdeletion and insertion polymorphisms (Indel), copy number variation(CNV), microsatellite markers or short tandem repeats and structuralvariation. Somatic variant calling is the effort to identify variantspresent at low frequency in the DNA sample. Somatic variant calling isof interest in the context of cancer treatment. Cancer is caused by anaccumulation of mutations in DNA. A DNA sample from a tumor is generallyheterogeneous, including some normal cells, some cells at an early stageof cancer progression (with fewer mutations), and some late-stage cells(with more mutations). Because of this heterogeneity, when sequencing atumor (e.g., from an FFPE sample), somatic mutations will often appearat a low frequency. For example, a SNV might be seen in only 10% of thereads covering a given base. A variant that is to be classified assomatic or germline by the variant classifier is also referred to hereinas the “variant under test”.

The term “variant frequency” represents the relative frequency of anallele (variant of a gene) at a particular locus in a population,expressed as a fraction or percentage. For example, the fraction orpercentage may be the fraction of all chromosomes in the population thatcarry that allele. By way of example, sample variant frequencyrepresents the relative frequency of an allele/variant at a particularlocus/position along a genomic sequence of interest over a “population”corresponding to the number of reads and/or samples obtained for thegenomic sequence of interest from an individual. As another example, abaseline variant frequency represents the relative frequency of anallele/variant at a particular locus/position along one or more baselinegenomic sequences where the “population” corresponding to the number ofreads and/or samples obtained for the one or more baseline genomicsequences from a population of normal individuals.

The term “variant allele frequency (VAF)” refers to the percentage ofsequenced reads observed matching the variant divided by the overallcoverage at the target position. VAF is a measure of the proportion ofsequenced reads carrying the variant.

The terms “position”, “designated position”, and “locus” refer to alocation or coordinate of one or more nucleotides within a sequence ofnucleotides. The terms “position”, “designated position”, and “locus”also refer to a location or coordinate of one or more base pairs in asequence of nucleotides.

The term “threshold” herein refers to a numeric or non-numeric valuethat is used as a cutoff to characterize a sample, a nucleic acid, orportion thereof (e.g., a read). A threshold may be varied based uponempirical analysis. The threshold may be compared to a measured orcalculated value to determine whether the source giving rise to suchvalue suggests should be classified in a particular manner. Thresholdvalues can be identified empirically or analytically. The choice of athreshold is dependent on the level of confidence that the user wishesto have to make the classification. The threshold may be chosen for aparticular purpose (e.g., to balance sensitivity and selectivity). Asused herein, the term “threshold” indicates a point at which a course ofanalysis may be changed and/or a point at which an action may betriggered. A threshold is not required to be a predetermined number.Instead, the threshold may be, for instance, a function that is based ona plurality of factors. The threshold may be adaptive to thecircumstances. Moreover, a threshold may indicate an upper limit, alower limit, or a range between limits.

System

FIG. 1 is a block diagram that shows various aspects of the technologydisclosed. We describe a system and various implementations ofefficiently comparing sequencing results. The system and processes aredescribed with reference to FIG. 1 . Because FIG. 1 is an architecturaldiagram, certain details are intentionally omitted to improve theclarity of the description.

The system contains the following engines: phasing encoder 102,unphasing encoder 104, sequencer 106, reference array generator 110,hash generator 114, hash sorter 118, global genome hasher 122, locationsensitive hasher 126, and location tagged hasher 130.

The system contains the following databases: reference data 112,sequencing results 108, hashes 116, sorted hashes 120, subregiondistances 132, distance value vectors 128, and global distance values124.

In some implementations, the system shown in FIG. 1 can be part of aclient, which is deployable to a smartphone or a computer such as alaptop or workstation.

The modules of the system in FIG. 1 can be implemented in hardware orsoftware, and need not be divided up in precisely the same blocks asshown in FIG. 1 . Some of the modules can also be implemented ondifferent processors or computers, or spread among a number of differentprocessors or computers. In addition, it will be appreciated that someof the modules can be combined, operated in parallel or in a differentsequence than that shown in FIG. 1 without affecting the functionsachieved. Also as used herein, the term “module” can include“sub-modules”, which themselves can be considered to constitute modules.The blocks in FIG. 1 , designated as modules, can also be thought of asflowchart steps in a method. A module also need not necessarily have allits code disposed contiguously in memory; some parts of the code can beseparated from other parts of the code with code from other modules orother functions disposed in between.

The interconnections of the elements of the system are now described.The public network(s) 115 couples the engines and the databases, all incommunication with each other (indicated by solid double-arrowed lines).The actual communication path can be point-to-point over public and/orprivate networks. Some items, such a client, might be deliveredindirectly, e.g., via an application store (not shown). Thecommunications can occur over a variety of networks, e.g., privatenetworks, VPN, MPLS circuit, or Internet, and can use appropriateapplication programming interfaces (APIs) and data interchange formats,e.g., Representational State Transfer (REST), JavaScript Object Notation(JSON), Extensible Markup Language (XML), Simple Object Access Protocol(SOAP), Java Message Service (JMS), and/or Java Platform Module System.All of the communications can be encrypted. The communication isgenerally over a network such as the LAN (local area network), WAN (widearea network), telephone network (Public Switched Telephone Network(PSTN), Session Initiation Protocol (SIP), wireless network,point-to-point network, star network, token ring network, hub network,Internet, inclusive of the mobile Internet, via protocols such as EDGE,3G, 4G LTE, Wi-Fi, and WiMAX. Additionally, a variety of authorizationand authentication techniques, such as username/password, OpenAuthorization (OAuth), Kerberos, SecureID, digital certificates andmore, can be used to secure the communications.

Phased and Unphased Encodings

FIG. 2 illustrates a phased encoding scheme with sixteen phased pairingsthat are used to encode the variant data. The phased encoding isoperationalized by the phasing encoder 102. FIG. 3 shows an unphasedencoding scheme with ten unphased pairings that can also be used toencode the variant data. The unphased encoding is operationalized by theunphasing encoder 104.

The sixteen phased pairings preserve the ordering of the alleles. Forexample, phased encoding translates alleles “AC” to “B” and alleles “CA”to “E”. In contrast, the ten unphased pairings do not distinguishbetween “AC” and “CA” and translate them both to “B”. The technologydisclosed uses the phased encoding to implement phased hashing. Inphased hashing, the hashes are generated from phased variant files andcan be applied on phased and unphased genomic data. In someimplementations, phased location sensitive hashing can be used toquickly phase unphased genomes and imputate in subset reference genomesthe variants nearby or within the genomic locations contained in thehashes.

Variant Data

FIG. 4 depicts first and second sequenced files that contain variantsoccurring at different carriers and at different carrier positions. Inthe illustrated implementation, the first sequenced file or output 410belongs to a first individual named Jan Andriessens and the secondsequenced file or output 412 belongs to a second individual named LindaAndriessens. Each sequenced file can contain variants ranging from tenthousand to three million. The sequenced files can be accessed fromgenomic sources such as 23&ME™ and Diagnomics™. The variants can bethose variants that have highest observed frequency (for example, asdetermined from minor and/or major allele frequency). The sequencedfiles can identify the variants by reference SNP cluster ID (Rsid) 402,chromosome 404, chromosome position 406, and base content of the alleles408. The sequenced files can be generated by the sequencer 106 (e.g.,Illumina™, IonTorrent™) and stored in the sequencing results database108. Once uploaded to a client

Reference Array

FIG. 5 illustrates a reference array 502 for those carrier positionsthat are shared or common between the first and second sequenced files410 and 412. In one implementation, the reference array 502 is generatedby the reference array generator 110. In one implementation, the lengthof the reference array 502 can range from one hundred thousand to onemillion base positions and can be configured depending on the analysis.In one implementation, the reference array can be ordered by carriersand by carrier positions, as depicted in FIG. 5 .

FIG. 5 also illustrates first and second sequences 504 and 506respectively generated from the first and second sequenced files 410 and412 based on the reference array 502. The first and second sequences 504and 506 are independently generated for the two individuals by using thereference array 502 as a template to look up the respective base valuesthat the two individuals have in the first and second sequenced files410 and 412 at the base positions identified by the reference array 502.As a result, the first and second sequences 504 and 506 have differentbase values, which are translated by the phased encoding scheme of FIG.2 . Accordingly, the first and second sequences 504 and 506 contain thetranslated phased encodings ranging from “A” to “P”, as shown in FIG. 2. In one implementation, the first and second sequences 504 and 506 arestored in the reference database 112.

Hash Generation

A DNA hash is a subset of DNA patterns with a fixed or variable lengththat occur in a genome. These can be used to match with another DNA hashfrom another genome. Patterns typically occur only a few times in thegenome. A distance value can be determined by calculating the percentageof matching patterns between two hashes. The length of the patterns andthe maximum (and minimum) hits in a genome can vary based on the desiredapplication.

Hashes can be generated on reference genomes and subsets of them. Ingeneral, they are the intersection of available positions on one ormultiple genomes, ordered by chromosome and chromosomal position.Flexible reference genome are key to a broad range of genomic queries.For example, a subset of genomic positions related to a trait can form anew reference genome to address that specific trait.

FIG. 6 shows how hashes are generated over a selected pattern length 602of positions in the reference array 502 to independently producenon-unique window hashes for base patterns in the first and secondsequences 504 and 506. The hashes are generated by the hash function604, which is a cryptographic algorithm such as SHA-1, SHA-2, SHA-256,and SHA-384. The hash function 604 is applied to the translated phasedencodings in the first and second sequences 504 and 506 (stored in thereference database 112). In one implementation, the selected patternlength 602 of positions can range from fifteen to forty bases. In someimplementations, the selected pattern length 602 of positions isselected based on the length of the reference array 502. In otherimplementations, the pattern length 602 is selected based on theanalysis being conducted. The window hashes are separately andindependently generated over the pattern length 602 for patterns in thefirst and second sequences 504 and 506 and are stored in the hashesdatabase 116.

Hash Sorting

Once the window hashes are generated for the first and second sequences504 and 506, they are stored based on their repeat or occurrencefrequency 702. That is, only those hash windows are selected that occurless than a ceiling number of times. In one implementation, the ceilingnumber of times ranges from one to ten and can be configured dependingon the analysis. The hash sorting is performed by the hash sorter 118and stored in the sorted hashes database 120.

For the first and second sequences 504 and 506, once those window hashesare identified that respectively occur less than a ceiling number oftimes, then they can be compared between the first and second sequences504 and 506 using a variety of analysis-specific techniques, includingglobal genome hashing, location sensitive hashing, and location taggedhashing.

Global Genome Hashing

Global genome hashing generates a global hash across the genome. Globalgenome hashing is implemented by the global genome hasher 122, whichoperates on the sorted hashes 116. When two hashes are compared, aglobal distance value is calculated and stored in the global distancevalues database 124. The global genome hasher 122 accesses the windowhashes that occur less than a ceiling number of times and compares theselected window hashes to identify common window hashes between thefirst and second sequences. The global genome hasher 122 then determinesa similarity measure between the first and second sequences based on thecommon window hashes. In one implementation, the similarity measure isdetermined by a distance formula defined as

$\frac{1 - numberofcommonwindowhashes}{numberofuniquewindowhashes}$

.

Global genome hashing is used by the technology disclosed for fast DNAcomparison without privacy loss. Global genome hashing provides a fast,anonymous, and robust way of calculating distances between genomes. Thehash is only a fraction (10-1000 kb) of the total genome, but stillallows to calculate distances between genomes in a couple ofmilliseconds. Some example applications of global genome hashing includegenetic distance trees (FIG. 8 ), online and wireless mobile DNA searchengines, and genealogy databases.

Location Sensitive Hashing

Location sensitive hashing generates a global hash matrix withindividual hashes within defined partitions on the reference genome.When two location sensitive hashing matrices are compared, a distancevalue vector is calculated that allows region specific comparisonsbetween genomes. Location sensitive hashing is implemented by thelocation sensitive hasher 126, which also operates on the sorted hashes116. The distance value vector is stored in the distance value vectorsdatabase 128.

The location sensitive hasher 126 accesses the window hashes that occurless than a ceiling number of times and compares the selected windowhashes between the first and second sequences on a bin-by-bin basis suchthat a first set of selected window hashes produced for base patterns ina given bin in the first sequenced output are compared only to a seconda set of selected window hashes produced for base patterns in the givenbin in the second sequenced output. The location sensitive hasher 126can then identify common window hashes for each bin in the first andsecond sequences based on the comparing and further determine asimilarity measure for each bin based on the common window hashes. Thelocation sensitive hasher 126 can also require that the selected windowhashes in the first set completely match with the corresponding selectedwindow hashes in the second set. The bins are defined for the first andsecond sequenced outputs on a carrier-by-carrier basis by regionpartitions 704. Each bin can contain five hundred to thousand variants.In other implementations, each bin can span across one hundred thousandto one million bases. In yet other implementations, each bin can spanacross multiple units (genes).

Location Tagged Hashing

Location tagged hashing generates a matrix of hashes with an exactgenomic location within the reference genome. When two location taggedhashing matrices are compared, distances for subregions can be measuredby looking for hash matches on the genomic locations within the region.Location tagged hashing is implemented by the location tagged hasher130, which also operates on the sorted hashes 116. The subregiondistance is stored in the subregion distances database 132. The locationtagged hasher 130 accesses the window hashes that occur less than aceiling number of times and compares the selected window hashes betweenthe first and second sequences on a starting position basis such thatselected window hashes for base patterns having same start positions inthe read results are compared. In implementations, the startingpositions can be chromosomal positions or sites. The location sensitivehasher 126 can then identify common window hashes between the first andsecond sequences based on the comparing and further determine asimilarity measure between the first and second sequences based on thecommon window hashes.

In one implementation, for the bin-wise similarity measures, the systemcan require that the selected window hashes between the correspondingbins substantially match. The substantial matching can be determined bya threshold number of hits between the corresponding bins. The thresholdis a hyperparameter that can be configured for different analysis. Inone implementation, the threshold used for identifying ethnic ancestryor ethnic origins is lower than that used for determining inheritedtraits.

Based on the bin-wise and/or starting position-wise similarity measures,the technology disclosed determines a percentage of shared bases betweenthe sequencing results. In some implementations, the percentage ofshared bases can be determined on a carrier-by-carrier basis.

Distance Tree Visualization

FIG. 8 is one implementation of a distance tree visualization 802. Insome implementations, the technology disclosed can use the percentage ofshared bases to identify common ancestors and close and distantrelatives. In one implementation, the distance tree visualization 802can be generated based on the percentage of shared bases to identify thedegree of relatedness between individuals.

Bin-Wise Genome Comparison

FIG. 9 shows an example bin-wise comparison 902 between genomes of twoindividuals as implemented by the location sensitive hashing. In someimplementations, the technology disclosed can use the percentage ofshared bases to determine traits inherited from an ancestor. Forexample, if a particular chromosome, a particular gene, or a particularpart of the gene is known to be associated with a disease and anancestor of an individual had that disease, then the percentage ofshared bases can identify whether the individual inherited thepathogenic bases from the ancestor and thus is susceptible to thedisease.

Ethnic Origination Discovery

FIG. 10 illustrates one implementation of determining ethnic ancestry orethnic origins 1002 of an individual using the location sensitivehashing and/or the location tagged hashing. Based on the percentage ofshared bases, the system can identify ethnic ancestry or ethnic originsof the given individual across multiple ethnicities and sub-ethnicities.For example, known template read results representing ethnicities likeEuropean, Asian, and African and sub-ethnicities like Norther European,British, Central European, Italian, Spanish/Portugese, East Asian, andSouth Asian can be compared against the given individual’s read resultsto determine what percentage of the given individual’s genome originatesfrom different ethnic and sub-ethnic groups.

Genome Browser

FIGS. 11A, 11B, and 11C show one implementation of a genomic browser1104 that presents comparative visualizations of genomic content of twoindividuals 1102. The genomic browser 1104 visualizes base content ofthe various chromosomes 1112 of the two individuals 1102, with zoom-inand zoom-out options that change the size of the based content beinganalyzed and compared between the two individuals 1102.

Computer System

FIG. 12 is a simplified block diagram of a computer system that can beused to implement the technology disclosed. Computer system 1210typically includes one or more processors 1214 that communicate with anumber of peripheral devices via bus subsystem 1212. These peripheraldevices can include a storage subsystem 1224 including, for example, amemory subsystem 1226 and a file storage subsystem 1228, user interfaceinput devices 1222, user interface output devices 1218, and a networkinterface 1216. The input and output devices allow user interaction withthe computer system 1210. The network interface 1216 provides aninterface to outside networks, including an interface to correspondinginterface devices in other computer systems.

In one implementation, one or more components of FIG. 1 are communicablylinked to the storage subsystem 1224 and the user interface inputdevices 1222.

The user interface input devices 1222 can include a keyboard; pointingdevices such as a mouse, trackball, touchpad, or graphics tablet; ascanner; a touch screen incorporated into the display; audio inputdevices such as voice recognition systems and microphones; and othertypes of input devices. In general, use of the term “input device” isintended to include all possible types of devices and ways to inputinformation into the computer system 1210.

The user interface output devices 1218 can include a display subsystem,a printer, a fax machine, or non-visual displays such as audio outputdevices. The display subsystem can include a cathode ray tube (CRT), aflat-panel device such as a liquid crystal display (LCD), a projectiondevice, or some other mechanism for creating a visible image. Thedisplay subsystem can also provide a non-visual display such as audiooutput devices. In general, use of the term “output device” is intendedto include all possible types of devices and ways to output informationfrom the computer system 1210 to the user or to another machine orcomputer system.

The storage subsystem 1224 stores programming and data constructs thatprovide the functionality of some or all of the modules and methodsdescribed herein. These software modules are generally executed by theprocessors 1214 alone or in combination with other processors.

The memory subsystem 1226 used in the storage subsystem 1224 can includea number of memories including a main random access memory (RAM) 1234for storage of instructions and data during program execution and a readonly memory (ROM) 1232 in which fixed instructions are stored. The filestorage subsystem 1228 can provide persistent storage for program anddata files, and can include a hard disk drive, a floppy disk drive alongwith associated removable media, a CD-ROM drive, an optical drive, orremovable media cartridges. The modules implementing the functionalityof certain implementations can be stored by the file storage subsystem1228 in the storage subsystem 1224, or in other machines accessible bythe processors 1214.

The bus subsystem 1212 provides a mechanism for letting the variouscomponents and subsystems of the computer system 1210 communicate witheach other as intended. Although the bus subsystem 1212 is shownschematically as a single bus, alternative implementations of the bussubsystem 1212 can use multiple busses.

Application server 1220 can be a framework that allows the applicationsof the computer system 1210 to run, such as the hardware and/orsoftware, e.g., the operating system.

The computer system 1210 can be of varying types including aworkstation, server, computing cluster, blade server, server farm, orany other data processing system or computing device. Due to theever-changing nature of computers and networks, the description of thecomputer system 1210 depicted in FIG. 12 is intended only as oneexample. Many other configurations of the computer system 1210 arepossible having more or fewer components than the computer systemdepicted in FIG. 12 .

Any data structures and code described or referenced above are storedaccording to many implementations on a computer-readable storage medium,which may be any device or medium that can store code and/or data foruse by a computer system. This includes, but is not limited to, volatilememory, non-volatile memory, application-specific integrated circuits(ASICs), field-programmable gate arrays (FPGAs), magnetic and opticalstorage devices such as disk drives, magnetic tape, CDs (compact discs),DVDs (digital versatile discs or digital video discs), or other mediacapable of storing computer-readable media now known or later developed.

Some Particular Implementations

We describe a system and various implementations of efficientlycomparing sequencing results. One or more features of an implementationcan be combined with the base implementation. Implementations that arenot mutually exclusive are taught to be combinable. One or more featuresof an implementation can be combined with other implementations. Thisdisclosure periodically reminds the user of these options. Omission fromsome implementations of recitations that repeat these options should notbe taken as limiting the combinations taught in the preceding sections -these recitations are hereby incorporated forward by reference into eachof the following implementations.

In one implementation, the technology disclosed presents a system. Thesystem runs on one or more processors coupled to memory. The memory isloaded with computer instructions to efficiently compare read results.The instructions, when executed on the processors, implement thefollowing actions.

First, the system generates a reference array of variant data forlocations that are shared between read results which are to be compared.In one implementation, the length of the reference array can range fromone hundred thousand to one million base positions. In oneimplementation, the reference array can be ordered by carriers and bycarrier positions, as depicted in FIG. 5 .

The system then generates hashes over a selected pattern length ofpositions in the reference array to independently produce non-uniquewindow hashes for base patterns in the read results. In oneimplementation, the selected pattern length of positions can range fromfifteen to forty bases.

The system then selects for comparison window hashes that occur lessthan a ceiling number of times. In one implementation, the ceilingnumber of times ranges from one to ten.

The system then compares the selected window hashes to identify commonwindow hashes between the read results.

The system then determines a similarity measure for the read resultsbased on the common window hashes. In one implementation, the similaritymeasure can be determined by a distance formula defined as

$\frac{1 - number\mspace{6mu} of\mspace{6mu} common\mspace{6mu} window\mspace{6mu} hashes}{number\mspace{6mu} of\mspace{6mu} unique\mspace{6mu} window\mspace{6mu} hashed}$

.

This system implementation and other systems disclosed optionallyinclude one or more of the following features. System can also includefeatures described in connection with methods disclosed. In the interestof conciseness, alternative combinations of system features are notindividually enumerated. Features applicable to systems, methods, andarticles of manufacture are not repeated for each statutory class set ofbase features. The reader will understand how features identified inthis section can readily be combined with base features in otherstatutory classes.

The variant data can contain those variants that have highest observedfrequency (for example, as determined from minor and/or major allelefrequency). In one implementation, the variant data can be identified bysixteen phased pairings, as depicted in FIG. 2 . In otherimplementations, the variant data can be identified by ten unphasedpairings, as depicted in FIG. 3 .

In one implementation, the pattern length of positions can be selectedbased on the length of the reference array.

In some implementations, the read results can be partitioned into bins.In such implementations, the system compares the selected window hashesbetween the read results on a bin-by-bin basis such that selected windowhashes for base patterns occurring in corresponding bins in the readresults are compared. Then, based on the comparing, the systemidentifies common window hashes between the corresponding bins. Further,the system determines a similarity measure for the corresponding binsbased on the common window hashes.

In one implementation, the system requires that the selected windowhashes between the corresponding bins completely match. Based on thebin-wise similarity measures, the system determines a percentage ofshared bases between the read results. In some implementations, thepercentage of shared bases can be determined on a carrier-by-carrierbasis.

In some implementations, the system can use the percentage of sharedbases to determine traits inherited from an ancestor. For example, if aparticular chromosome, a particular gene, or a particular part of thegene is known to be associated with a disease and an ancestor of anindividual had that disease, then the percentage of shared bases canidentify whether the individual inherited the pathogenic bases from theancestor and thus is susceptible to the disease.

In some implementations, the system can use the percentage of sharedbases to identify common ancestors and close and distant relatives. Inone implementation, a distance tree visualization can be generated basedon the percentage of shared bases to identify the degree of relatednessbetween individuals.

In some implementations, based on the bin-wise similarity measures, thesystem can determine a percentage of shared bases between a givenindividual’s read results and ethnicity-specific read results. Based onthe percentage of shared bases, the system can identify ethnic ancestryor ethnic origins of the given individual across multiple ethnicitiesand sub-ethnicities. For example, known template read resultsrepresenting ethnicities like European, Asian, and African andsub-ethnicities like Norther European, British, Central European,Italian, Spanish/Portugese, East Asian, and South Asian can be comparedagainst the given individual’s read results to determine what percentageof the given individual’s genome originates from different ethnic andsub-ethnic groups.

In one implementation, for the bin-wise similarity measures, the systemcan require that the selected window hashes between the correspondingbins substantially match. The substantial matching can be determined bya threshold number of hits between the corresponding bins. The thresholdis a hyperparameter that can be configured for different analysis. Inone implementation, the threshold used for identifying ethnic ancestryor ethnic origins is lower than that used for determining inheritedtraits.

The bins can be defined for the read results on a carrier-by-carrierbasis. In one implementation, each bin can contain five hundred tothousand variants. In another implementation, each bin can span acrossone hundred thousand to one million bases. In yet anotherimplementation, each bin can span across multiple units.

In some implementations, the system compares the selected window hashesbetween the read results on a starting position basis such that selectedwindow hashes for base patterns having same start positions in the readresults are compared. Based on the comparison, the system identifiescommon window hashes between the read results. The system thendetermines a similarity measure between the read results based on thecommon window hashes.

In one implementation, the system determines a percentage of sharedbases between the read results based on the starting position-wisesimilarity measures. In some implementations, the percentage of sharedbases can be determined on a carrier-by-carrier basis.

In one implementation, the system determines inherited traits based onthe percentage of shared bases as determined from the startingposition-wise similarity measures. In another implementation, the systemidentifies common ancestors and close and distant relatives based on thepercentage of shared bases as determined from the starting position-wisesimilarity measures. In yet another implementation, based on thestarting position-wise similarity measures, the system determines apercentage of shared bases between a given individual’s read results andethnicity-specific read results and identifies ethnic ancestry or ethnicorigins of the given individual based on the percentage of shared bases.In yet further implementations, based on the starting position-wisesimilarity measures, the system generates a distance tree visualizationbetween the read results.

Other implementations may include a non-transitory computer readablestorage medium storing instructions executable by a processor to performactions of the system described above. Each of the features discussed inthe particular implementation section for other implementations applyequally to this implementation. As indicated above, all the otherfeatures are not repeated here and should be considered repeated byreference.

In one implementation, the technology disclosed presents acomputer-implemented method of efficiently comparing read results.

The method includes generating a reference array of variant data forlocations shared between read results to be compared.

The method includes generating hashes over a selected pattern length ofpositions in the reference array to independently produce non-uniquewindow hashes for base patterns in the read results.

The method includes selecting for comparison window hashes that occurless than a ceiling number of times.

The method includes comparing the selected window hashes to identifycommon window hashes between the read results.

The method includes determining a similarity measure for the readresults based on the common window hashes.

Other implementations may include a non-transitory computer readablestorage medium (CRM) storing instructions executable by a processor toperform the computer-implemented method described above. Yet anotherimplementation may include a system including memory and one or moreprocessors operable to execute instructions, stored in the memory, toperform the computer-implemented method described above. Each of thefeatures discussed in the particular implementation section for otherimplementations apply equally to this implementation. As indicatedabove, all the other features are not repeated here and should beconsidered repeated by reference.

In another implementation, the technology disclosed presents a system.The system runs on one or more processors coupled to memory. The memoryis loaded with computer instructions to efficiently compare sequencedfiles. The instructions, when executed on the processors, implement thefollowing actions.

First, the system accesses a first sequenced file and a second sequencedfile. The first sequenced file can belong to a first individual and thesecond sequenced file can belong to a second individual. The first andsecond sequenced files contain variants occurring at different carriersand at different carrier positions, as depicted in FIG. 4 . The variantscan be those variants that have highest observed frequency (for example,as determined from minor and/or major allele frequency). In oneimplementation, the variants are identified by sixteen phased pairings,as depicted in FIG. 2 . In other implementations, the variants areidentified by ten unphased pairings, as depicted in FIG. 3 .

The system then generates a reference array for those carrier positionsthat are shared between the first and second sequenced files, as shownin FIG. 5 . In one implementation, the length of the reference array canrange from one hundred thousand to one million base positions. In oneimplementation, the reference array can be ordered by carriers and bycarrier positions, as depicted in FIG. 5 .

The system then, based on the reference array, generates a firstsequence from the first sequenced file and a second sequence from thesecond sequenced file, as shown in FIG. 5 .

The system then generates hashes over a selected pattern length ofpositions in the reference array to independently produce non-uniquewindow hashes for base patterns in the first and second sequences. Inone implementation, the selected pattern length of positions can rangefrom fifteen to forty bases.

The system then selects for comparison window hashes that occur lessthan a ceiling number of times.

The system then compares the selected window hashes to identify commonwindow hashes between the first and second sequences.

The system then determines a similarity measure between the first andsecond sequences based on the common window hashes. In oneimplementation, the similarity measure can be determined by a distanceformula defined as

$\frac{1 - number\mspace{6mu} of\mspace{6mu} common\mspace{6mu} window\mspace{6mu} hashes}{number\mspace{6mu} of\mspace{6mu} unique\mspace{6mu} window\mspace{6mu} hashes}.$

.

In some implementations, based on the similarity measure, the systemgenerates a distance tree between the first and second sequences.

Each of the features discussed in the particular implementation sectionfor other implementations apply equally to this implementation. Asindicated above, all the other features are not repeated here and shouldbe considered repeated by reference.

In one implementation, the technology disclosed presents acomputer-implemented method of efficiently comparing sequenced files.

The method includes accessing a first sequenced file and a secondsequenced file. The first sequenced file can belong to a firstindividual and the second sequenced file can belong to a secondindividual. The first and second sequenced files contain variantsoccurring at different carriers and at different carrier positions, asdepicted in FIG. 4 . The variants can be those variants that havehighest observed frequency (for example, as determined from minor and/ormajor allele frequency). In one implementation, the variants areidentified by sixteen phased pairings, as depicted in FIG. 2 . In otherimplementations, the variants are identified by ten unphased pairings,as depicted in FIG. 3 .

The method includes generating a reference array for those carrierpositions that are shared between the first and second sequenced files,as shown in FIG. 5 . In one implementation, the length of the referencearray can range from one hundred thousand to one million base positions.In one implementation, the reference array can be ordered by carriersand by carrier positions, as depicted in FIG. 5 .

The method includes, based on the reference array, generating a firstsequence from the first sequenced file and a second sequence from thesecond sequenced file, as shown in FIG. 5 .

The method includes generating hashes over a selected pattern length ofpositions in the reference array to independently produce non-uniquewindow hashes for base patterns in the first and second sequences.

The method includes selecting for comparison window hashes that occurless than a ceiling number of times.

The method includes comparing the selected window hashes to identifycommon window hashes between the first and second sequences.

The method includes determining a similarity measure between the firstand second sequences based on the common window hashes. In oneimplementation, the similarity measure can be determined by a distanceformula defined as

$\frac{1 - number\mspace{6mu} of\mspace{6mu} common\mspace{6mu} window\mspace{6mu} hashes}{number\mspace{6mu} of\mspace{6mu} unique\mspace{6mu} window\mspace{6mu} hashes}$

.

Other implementations may include a non-transitory computer readablestorage medium (CRM) storing instructions executable by a processor toperform the computer-implemented method described above. Yet anotherimplementation may include a system including memory and one or moreprocessors operable to execute instructions, stored in the memory, toperform the computer-implemented method described above. Each of thefeatures discussed in the particular implementation section for otherimplementations apply equally to this implementation. As indicatedabove, all the other features are not repeated here and should beconsidered repeated by reference.

In one implementation, the technology disclosed presents a system. Thesystem runs on one or more processors coupled to memory. The memory isloaded with computer instructions to efficiently compare sequencedoutputs. The instructions, when executed on the processors, implementthe following actions.

First, the system accesses a first sequenced output and a secondsequenced output. The first sequenced output can belong to a firstindividual and the second sequenced output can belong to a secondindividual. The first and second sequenced outputs contain variantsoccurring at different carriers and at different carrier positions, asdepicted in FIG. 4 . The variants can be those variants that havehighest observed frequency (for example, as determined from minor and/ormajor allele frequency). In one implementation, the variants areidentified by sixteen phased pairings, as depicted in FIG. 2 . In otherimplementations, the variants are identified by ten unphased pairings,as depicted in FIG. 3 .

The system then generates a reference array for those carrier positionsthat are shared between the first and second sequenced outputs, as shownin FIG. 5 . In one implementation, the length of the reference array canrange from one hundred thousand to one million base positions. In oneimplementation, the reference array can be ordered by carriers and bycarrier positions, as depicted in FIG. 5 .

The system then, based on the reference array, generates a firstsequence from the first sequenced output and a second sequence from thesecond sequenced output, as shown in FIG. 5 .

The system then generates hashes over a selected pattern length ofpositions in the reference array to independently produce non-uniquewindow hashes for base patterns in the first and second sequences. Inone implementation, the selected pattern length of positions can rangefrom fifteen to forty bases.

The system then selects for comparison window hashes that occur lessthan a ceiling number of times.

The system then compares the selected window hashes between the firstand second sequences on a starting position basis such that selectedwindow hashes for base patterns having same start positions in the readresults are compared. In some implementations, the system compares theselected window hashes between the first and second sequences on thestarting position basis such that a first selected window hash producedfor a base pattern having a given start position in the first sequenceis compared only to a second selected window hash produced for a basepattern having the given start position in the second sequence.

The system then identifies common window hashes between the first andsecond sequences based on the comparing.

The system then determines a similarity measure between the first andsecond sequences based on the common window hashes. In oneimplementation, the similarity measure can be determined by a distanceformula defined as

$\frac{1 - number\mspace{6mu} of\mspace{6mu} common\mspace{6mu} window\mspace{6mu} hashes}{number\mspace{6mu} of\mspace{6mu} unique\mspace{6mu} window\mspace{6mu} hashes}.$

.

In some implementations, based on the similarity measure, the systemgenerates a distance tree between the first and second sequences.

Each of the features discussed in the particular implementation sectionfor other implementations apply equally to this implementation. Asindicated above, all the other features are not repeated here and shouldbe considered repeated by reference.

In one implementation, the technology disclosed presents acomputer-implemented method of efficiently comparing sequenced outputs.

The method includes accessing a first sequenced output and a secondsequenced output. The first sequenced output can belong to a firstindividual and the second sequenced output can belong to a secondindividual. The first and second sequenced outputs contain variantsoccurring at different carriers and at different carrier positions, asdepicted in FIG. 4 . The variants can be those variants that havehighest observed frequency (for example, as determined from minor and/ormajor allele frequency). In one implementation, the variants areidentified by sixteen phased pairings, as depicted in FIG. 2 . In otherimplementations, the variants are identified by ten unphased pairings,as depicted in FIG. 3 .

The method includes generating a reference array for those carrierpositions that are shared between the first and second sequencedoutputs, as shown in FIG. 5 . In one implementation, the length of thereference array can range from one hundred thousand to one million basepositions. In one implementation, the reference array can be ordered bycarriers and by carrier positions, as depicted in FIG. 5 .

The method includes, based on the reference array, generating a firstsequence from the first sequenced output and a second sequence from thesecond sequenced output, as shown in FIG. 5 .

The method includes generating hashes over a selected pattern length ofpositions in the reference array to independently produce non-uniquewindow hashes for base patterns in the first and second sequences.

The method includes selecting for comparison window hashes that occurless than a ceiling number of times.

The method includes comparing the selected window hashes between thefirst and second sequences on a starting position basis such thatselected window hashes for base patterns having same start positions inthe read results are compared. In some implementations, the methodincludes comparing the selected window hashes between the first andsecond sequences on the starting position basis such that a firstselected window hash produced for a base pattern having a given startposition in the first sequence is compared only to a second selectedwindow hash produced for a base pattern having the given start positionin the second sequence.

The method includes identifying common window hashes between the firstand second sequences based on the comparing.

The method includes determining a similarity measure between the firstand second sequences based on the common window hashes. In oneimplementation, the similarity measure can be determined by a distanceformula defined as

$\frac{1 - number\mspace{6mu} of\mspace{6mu} common\mspace{6mu} window\mspace{6mu} hashes}{number\mspace{6mu} of\mspace{6mu} unique\mspace{6mu} window\mspace{6mu} hashes}.$

.

Other implementations may include a non-transitory computer readablestorage medium (CRM) storing instructions executable by a processor toperform the computer-implemented method described above. Yet anotherimplementation may include a system including memory and one or moreprocessors operable to execute instructions, stored in the memory, toperform the computer-implemented method described above. Each of thefeatures discussed in the particular implementation section for otherimplementations apply equally to this implementation. As indicatedabove, all the other features are not repeated here and should beconsidered repeated by reference.

In one implementation, the technology disclosed presents a system. Thesystem runs on one or more processors coupled to memory. The memory isloaded with computer instructions to efficiently compare sequencedoutputs. The instructions, when executed on the processors, implementthe following actions.

First, the system accesses a first sequenced output and a secondsequenced output. The first sequenced output can belong to a firstindividual and the second sequenced output can belong to a secondindividual. The first and second sequenced outputs contain variantsoccurring at different carriers and at different carrier positions andare partitioned into bins. The variants can be those variants that havehighest observed frequency (for example, as determined from minor and/ormajor allele frequency). In one implementation, the variants areidentified by sixteen phased pairings, as depicted in FIG. 2 . In otherimplementations, the variants are identified by ten unphased pairings,as depicted in FIG. 3 .

The system then generates a reference array for those carrier positionsthat are shared between the first and second sequenced outputs, as shownin FIG. 5 . In one implementation, the length of the reference array canrange from one hundred thousand to one million base positions. In oneimplementation, the reference array can be ordered by carriers and bycarrier positions, as depicted in FIG. 5 .

The system then, based on the reference array, generates a firstsequence from the first sequenced output and a second sequence from thesecond sequenced output, as shown in FIG. 5 .

The system then generates hashes over a selected pattern length ofpositions in the reference array to independently produce non-uniquewindow hashes for base patterns in the first and second sequences. Inone implementation, the selected pattern length of positions can rangefrom fifteen to forty bases.

The system then selects for comparison window hashes that occur lessthan a ceiling number of times.

The system then compares the selected window hashes between the firstand second sequences on a bin-by-bin basis such that a first set ofselected window hashes produced for base patterns in a given bin in thefirst sequenced output are compared only to a second a set of selectedwindow hashes produced for base patterns in the given bin in the secondsequenced output. In some implementations, the system requires that theselected window hashes in the first set completely match with thecorresponding selected window hashes in the second set.

The system then identifies common window hashes for each bin in thefirst and second sequences based on the comparing.

The system then determines a similarity measure for each bin based onthe common window hashes. In one implementation, the similarity measurecan be determined by a distance formula defined as

$\frac{1 - number\mspace{6mu} of\mspace{6mu} common\mspace{6mu} window\mspace{6mu} hashes}{number\mspace{6mu} of\mspace{6mu} unique\mspace{6mu} window\mspace{6mu} hashes}.$

.

In some implementations, based on the similarity measure, the systemgenerates a distance tree between the first and second sequences.

Each of the features discussed in the particular implementation sectionfor other implementations apply equally to this implementation. Asindicated above, all the other features are not repeated here and shouldbe considered repeated by reference.

In one implementation, the technology disclosed presents acomputer-implemented method of efficiently comparing sequenced outputs.

The method includes accessing a first sequenced output and a secondsequenced output. The first sequenced output can belong to a firstindividual and the second sequenced output can belong to a secondindividual. The first and second sequenced outputs contain variantsoccurring at different carriers and at different carrier positions andare partitioned into bins. The variants can be those variants that havehighest observed frequency (for example, as determined from minor and/ormajor allele frequency). In one implementation, the variants areidentified by sixteen phased pairings, as depicted in FIG. 2 . In otherimplementations, the variants are identified by ten unphased pairings,as depicted in FIG. 3 .

The method includes generating a reference array for those carrierpositions that are shared between the first and second sequencedoutputs, as shown in FIG. 5 . In one implementation, the length of thereference array can range from one hundred thousand to one million basepositions. In one implementation, the reference array can be ordered bycarriers and by carrier positions, as depicted in FIG. 5 .

The method includes, based on the reference array, generating a firstsequence from the first sequenced output and a second sequence from thesecond sequenced output, as shown in FIG. 5 .

The method includes generating hashes over a selected pattern length ofpositions in the reference array to independently produce non-uniquewindow hashes for base patterns in the first and second sequences.

The method includes selecting for comparison window hashes that occurless than a ceiling number of times.

The method includes comparing the selected window hashes between thefirst and second sequences on a bin-by-bin basis such that a first setof selected window hashes produced for base patterns in a given bin inthe first sequenced output are compared only to a second a set ofselected window hashes produced for base patterns in the given bin inthe second sequenced output.

The method includes identifying common window hashes for each bin in thefirst and second sequences based on the comparing.

The method includes determining a similarity measure for each bin basedon the common window hashes. In one implementation, the similaritymeasure can be determined by a distance formula defined as

$\frac{1 - number\mspace{6mu} of\mspace{6mu} common\mspace{6mu} window\mspace{6mu} hashes}{number\mspace{6mu} of\mspace{6mu} unique\mspace{6mu} window\mspace{6mu} hashes}.$

.

Other implementations may include a non-transitory computer readablestorage medium (CRM) storing instructions executable by a processor toperform the computer-implemented method described above. Yet anotherimplementation may include a system including memory and one or moreprocessors operable to execute instructions, stored in the memory, toperform the computer-implemented method described above. Each of thefeatures discussed in the particular implementation section for otherimplementations apply equally to this implementation. As indicatedabove, all the other features are not repeated here and should beconsidered repeated by reference.

The preceding description is presented to enable the making and use ofthe technology disclosed. Various modifications to the disclosedimplementations will be apparent, and the general principles definedherein may be applied to other implementations and applications withoutdeparting from the spirit and scope of the technology disclosed. Thus,the technology disclosed is not intended to be limited to theimplementations shown, but is to be accorded the widest scope consistentwith the principles and features disclosed herein. The scope of thetechnology disclosed is defined by the appended claims.

What is claimed is:
 1. A computer-implemented method comprising:accessing a first sequenced output and a second sequenced output,wherein the first sequenced output and the second sequenced outputcontain variants occurring at different carriers and at differentcarrier positions; generating hashes over a selected pattern length ofpositions for those carrier positions that are shared between the firstsequenced output and the second sequenced output to produce windowhashes for base patterns in a first sequence and a second sequence, andwherein the first sequence is based on the shared carrier positions andthe first sequenced output, the second sequence is based on the sharedcarrier positions and the second sequenced output, and the window hashesare non-unique; selecting those of the window hashes that occur lessthan a ceiling number of times; comparing the selected window hashesbetween the first sequence and the second sequence on a startingposition basis such that selected window hashes for base patterns havingsame start positions in the first sequenced output and the secondsequenced output are compared; identifying common window hashes betweenthe first sequence and the second sequence based on the comparing; anddetermining a similarity measure between the first sequence and thesecond sequence based on the common window hashes.
 2. Thecomputer-implemented method of claim 1, further comprising: based onstarting position-wise similarity measures, determining a percentage ofshared bases between the first sequenced output and the second sequencedoutput.
 3. The computer-implemented method of claim 2, wherein thepercentage of shared bases are determined on a carrier-by-carrier basis.4. The computer-implemented method of claim 3, further comprising:determining inherited traits based on the percentage of shared bases. 5.The computer-implemented method of claim 3, further comprising:identifying common ancestors and close and distant relatives based onthe percentage of shared bases.
 6. The computer-implemented method ofclaim 2, further comprising: based on the starting position-wisesimilarity measures, determining a percentage of shared bases between agiven individual’s sequence and an ethnicity-specific sequence; andidentifying ethnic ancestry of the given individual based on thepercentage of shared bases.
 7. The computer-implemented method of claim2, further comprising: based on the starting position-wise similaritymeasures, generating a distance tree between the first sequenced outputand the second sequenced output.
 8. The computer-implemented method ofclaim 1, wherein the variants are those variants that have highestobservation frequency.
 9. The computer-implemented method of claim 1,wherein the variants are identified by sixteen phased pairings.
 10. Thecomputer-implemented method of claim 1, wherein the variants areidentified by ten unphased pairings.
 11. The computer-implemented methodof claim 1, wherein the selected pattern length of positions ranges fromfifteen to forty bases.
 12. The computer-implemented method of claim 1,wherein the window hashes are produced independently.
 13. Thecomputer-implemented method of claim 1, further comprising providing azoom-in option and a zoom-out option of a genomic browser, and whereinthe zoom-in option and the zoom-out option change size based on size ofthe first sequence and the second sequence.
 14. The computer-implementedmethod of claim 1, wherein the similarity measure is determined by adistance formula defined as$\frac{1 - number\mspace{6mu} of\mspace{6mu} common\mspace{6mu} window\mspace{6mu} hashes}{number\mspace{6mu} of\mspace{6mu} unique\mspace{6mu} window\mspace{6mu} hashes} \cdot$.
 15. The computer-implemented method of claim 1, further comprising:comparing the selected window hashes between the first sequence and thesecond sequence on a starting position basis such that a first selectedwindow hash produced for a base pattern having a given start position inthe first sequence is compared only to a second selected window hashproduced for a base pattern having the given start position in thesecond sequence.
 16. A non-transitory computer readable storage mediumimpressed with computer program instructions, the instructions, whenexecuted on a processor, implement a method comprising: accessing afirst sequenced output and a second sequenced output, wherein the firstsequenced output and the second sequenced output contain variantsoccurring at different carriers and at different carrier positions;generating hashes over a selected pattern length of positions for thosecarrier positions that are shared between the first sequenced output andthe second sequenced output to produce window hashes for base patternsin a first sequence and a second sequence, and wherein the firstsequence is based on the shared carrier positions and the firstsequenced output, the second sequence is based on the shared carrierpositions and the second sequenced output, and the window hashes arenon-unique; selecting those of the window hashes that occur less than aceiling number of times; comparing the selected window hashes betweenthe first sequence and the second sequence on a starting position basissuch that selected window hashes for base patterns having same startpositions in the first sequenced output and the second sequenced outputare compared; identifying common window hashes between the firstsequence and the second sequence based on the comparing; and determininga similarity measure between the first sequence and the second sequencebased on the common window hashes.
 17. The non-transitory computerreadable storage medium of claim 16, wherein the method furthercomprises: based on starting position-wise similarity measures,determining a percentage of shared bases between the first sequencedoutput and the second sequenced output.
 18. The non-transitory computerreadable storage medium of claim 17, wherein the percentage of sharedbases are determined on a carrier-by-carrier basis.
 19. A systemcomprising one or more processors coupled to memory, the memory loadedwith computer instructions, the instructions, when executed on theprocessors, implement actions comprising: accessing a first sequencedoutput and a second sequenced output, wherein the first sequenced outputand the second sequenced output contain variants occurring at differentcarriers and at different carrier positions; generating hashes over aselected pattern length of positions for those carrier positions thatare shared between the first sequenced output and the second sequencedoutput to produce window hashes for base patterns in a first sequenceand a second sequence, and wherein the first sequence is based on theshared carrier positions and the first sequenced output, the secondsequence is based on the shared carrier positions and the secondsequenced output, and the window hashes are non-unique; selecting thoseof the window hashes that occur less than a ceiling number of times;comparing the selected window hashes between the first sequence and thesecond sequence on a starting position basis such that selected windowhashes for base patterns having same start positions in the firstsequenced output and the second sequenced output are compared;identifying common window hashes between the first sequence and thesecond sequence based on the comparing; and determining a similaritymeasure between the first sequence and the second sequence based on thecommon window hashes.
 20. The system of claim 18, wherein the actionsfurther comprise: based on starting position-wise similarity measures,determining a percentage of shared bases between the first sequencedoutput and the second sequenced output.